rs759557477

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006019.4(TCIRG1):ā€‹c.725A>Gā€‹(p.His242Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

TCIRG1
NM_006019.4 missense

Scores

4
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14
Variant links:
Genes affected
TCIRG1 (HGNC:11647): (T cell immune regulator 1, ATPase H+ transporting V0 subunit a3) This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCIRG1NM_006019.4 linkuse as main transcriptc.725A>G p.His242Arg missense_variant 8/20 ENST00000265686.8 NP_006010.2 Q13488-1A0A024R5E5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCIRG1ENST00000265686.8 linkuse as main transcriptc.725A>G p.His242Arg missense_variant 8/201 NM_006019.4 ENSP00000265686.3 Q13488-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000584
AC:
1
AN:
171270
Hom.:
0
AF XY:
0.0000109
AC XY:
1
AN XY:
91448
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000783
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000142
AC:
2
AN:
1411252
Hom.:
0
Cov.:
33
AF XY:
0.00000287
AC XY:
2
AN XY:
697536
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000395
Gnomad4 EAS exome
AF:
0.0000271
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000847
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive osteopetrosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylJun 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Uncertain
0.69
D;D;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Uncertain
0.090
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.6
D;D;D
REVEL
Pathogenic
0.72
Sift
Benign
0.038
D;T;T
Sift4G
Benign
0.21
T;T;T
Polyphen
0.98
D;.;.
Vest4
0.76
MutPred
0.50
Gain of MoRF binding (P = 0.0461);.;.;
MVP
0.96
MPC
0.41
ClinPred
0.76
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.40
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759557477; hg19: chr11-67811292; COSMIC: COSV55835327; COSMIC: COSV55835327; API